CN107715110B - Biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer and preparation method and application thereof - Google Patents
Biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer and preparation method and application thereof Download PDFInfo
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- 239000003504 photosensitizing agent Substances 0.000 title claims abstract description 85
- 238000002428 photodynamic therapy Methods 0.000 title claims abstract description 61
- 238000006065 biodegradation reaction Methods 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000002135 nanosheet Substances 0.000 claims abstract description 40
- 239000000243 solution Substances 0.000 claims abstract description 39
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
Abstract
The invention discloses a preparation method and application of a novel biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer. The preparation method comprises the following steps: (1) dispersing the black phosphorus nanosheets in an organic solvent to obtain a black phosphorus nanosheet solution; (2) dissolving bismuth salt in an organic solvent to obtain a bismuth salt solution; (3) and (3) adding the bismuth salt solution obtained in the step (2) into the black phosphorus nanosheet solution obtained in the step (1), standing, and centrifuging to obtain the biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer. The method has the advantages of simple process, easy operation, large sample preparation amount, short time consumption and good reproducibility, the prepared photosensitizer grows bismuth trioxide quantum dots on the surface of black phosphorus, retains the characteristics of the black phosphorus, increases the stability of the black phosphorus, is degradable in a physiological environment, can be induced by X rays to generate singlet oxygen, realizes a synergistic photodynamic effect, and can be applied to the fields of photoelectric devices, solar cells, lithium batteries, biomedicine and the like.
Description
Technical Field
The invention belongs to the field of novel nano materials, and particularly relates to a biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer as well as a preparation method and application thereof.
Background
According to global cancer report 2014 issued by the world health organization, the number of cancer patients and death cases is increased in 2012, reaching about 1400 million people, wherein nearly half of newly added cancer cases appear in asia. The world health organization predicts that cancer will continue to be the top ranking in the leaderboard of human killers in the next hundred years.
The photodynamic therapy is a new disease treatment technology, is a cold chemical reaction, only needs photosensitizer, oxygen and light, the photosensitizer is excited by light, and the photosensitizer transfers energy to the surrounding oxygen, thereby generating singlet oxygen with strong activity, killing or damaging cancer cells and achieving the purpose of treatment. Photodynamic therapy has gained extensive attention and research in recent years due to its low invasiveness and toxicity, non-drug resistance and other advantages compared to conventional radiotherapy. The existing photosensitizer needs to be excited by visible light or near infrared light, the penetration depth of the visible light or the near infrared light is only limited (1-5 mm), and the energy is low, so that the photosensitizer cannot effectively exert the treatment effect on deep malignant tumors. The photosensitizer used clinically is a compound of various porphyrins and derivatives thereof, is complex in component, is easily influenced by environmental factors in organisms, is not easy to control the photosensitive treatment effect, needs to be protected from light for 1-2 months after administration, brings inconvenience to life of patients, and simultaneously buries hidden dangers in the practical application of photodynamic therapy.
The X-ray has a large energy range and strong penetrating power, and can penetrate different depths of a human body. X-rays have therefore also attracted considerable attention in photodynamic therapy. Although the radioactive rays have a relatively direct killing and inhibiting effect on tumor cells, the radioactive rays still have relatively large toxic and side effects on normal tissues of a human body, and radiotherapy can only treat primary tumor bodies and still cannot kill tumor cells which are already metastasized. The chemotherapy technology is relatively mature at present, and the treatment means has good curative effect on primary tumor foci, metastatic foci and subclinical metastatic foci. Therefore, in the current treatment, the synchronous radiotherapy and chemotherapy has good effect and application prospect in the tumor treatment. However, during the course of radiotherapy, due to the hypoxic environment of the tumor, the tumor cells cannot be completely eradicated by the radiotherapy alone, and the tumor is not sensitive to X-ray tolerance. Therefore, the design and synthesis of the photosensitizer is simple, can efficiently utilize X rays with strong penetrating power, can degrade the photosensitizer in a physiological environment to play the synergistic anti-tumor effect of the photosensitizer and radiotherapy, has important significance, and is expected to promote the development of new clinical anti-tumor drugs.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a preparation method of a biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer.
The invention also aims to provide the biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer prepared by the method.
Still another object of the present invention is to provide the use of said biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer.
The purpose of the invention is realized by the following technical scheme: a method for preparing a biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer comprises the following steps:
(1) dispersing the black phosphorus nanosheets in an organic solvent to obtain a black phosphorus nanosheet solution;
(2) dissolving bismuth salt in an organic solvent to obtain a bismuth salt solution;
(3) and (3) adding the bismuth salt solution obtained in the step (2) into the black phosphorus nanosheet solution obtained in the step (1), standing, and centrifuging to obtain the biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer.
The black phosphorus nanosheet in the step (1) is obtained by stripping a black phosphorus crystal in a liquid phase; preferably prepared by the following method: and dispersing the black phosphorus powder into an organic solvent, performing ultrasonic treatment, centrifuging to remove precipitates, and centrifuging again to obtain the black phosphorus nanosheet.
The organic solvent is preferably N-methylpyrrolidone.
The ultrasonic treatment conditions are preferably as follows: the ultrasonic treatment is carried out at 1200W for 5 hours, and then the ultrasonic treatment is carried out at 1200W for 5 hours in an ice bath.
The conditions for removing the precipitate by centrifugation are preferably as follows: centrifuge at 7000 for 15 minutes.
The conditions for obtaining the black phosphorus nanometer by centrifugation are preferably as follows: centrifuge for 15 minutes at 12000 rpm.
The concentration of the black phosphorus nanosheet solution in the step (1) is 0-1 mg/mL; preferably 1-1000 mu g/mL; more preferably 10 to 50. mu.g/mL.
The organic solvent in the steps (1) and (2) is one or more of N-methylpyrrolidone, N, N-dimethylformamide, 1, 3-dimethyl-2-imidazolidinone, isopropanol, ethylene glycol, tetrahydrofuran and dimethyl sulfoxide.
The bismuth salt in the step (2) is soluble bismuth salt; preferably one or more of bismuth nitrate pentahydrate, bismuth acetate and bismuth citrate.
The concentration of the bismuth salt solution in the step (2) is 0-100 mM; preferably 1 to 100 mM; more preferably 8 to 25 mM.
The volume ratio of the bismuth salt solution to the black phosphorus nanosheet solution in the step (3) is 0-1: 1; preferably 2 to 21: 21.
the standing condition in the step (3) is as follows: standing for 0.5-8 hours at 4-80 ℃; the conditions for standing are preferably: standing for 0.5-8 hours at room temperature.
The centrifugation conditions in the step (3) are as follows: centrifuging at 8000-14000 rpm for 10-30 minutes; the conditions of centrifugation are preferably: centrifuge at 12000rpm for 15 minutes.
The biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer in the step (3) is formed by bismuth trioxide quantum dots on the surface of a black phosphorus nanosheet; the bismuth trioxide quantum dots are 5 +/-3 nm.
A biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer is prepared by the method of any one of the above.
The biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer can be applied to the fields of photoelectric devices, solar cells, lithium batteries and biomedicine.
The application of the biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer in preparing antitumor drugs.
The tumor includes human melanoma, non-small cell lung cancer, human cervical cancer, human gastric cancer, human liver cancer, breast cancer, nasopharyngeal carcinoma and brain glioma.
Compared with the prior art, the invention has the following advantages and effects:
1. in the invention, the black phosphorus is a semiconductor with a natural folded laminated structure as the most stable one of phosphorus allotropes, and the unique folded structure endows the black phosphorus with a plurality of unique physicochemical properties, such as direct band gap of the black phosphorus and electron mobility exceeding that of transition metal, and can reach 1,000cm2V-1s-1The above. The novel biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer prepared by the photosensitizer has good dispersibility, is stable in water, can be degraded in a physiological environment, can be induced by X-rays to generate singlet oxygen, has large treatment depth, and is slightly influenced by other factors in the physiological environment.
2. The preparation method comprises the steps of dispersing bismuth salt in solvents such as ethylene glycol, mixing bismuth salt solution and N-methylpyrrolidone solution of the black phosphorus nanosheet according to a certain proportion, standing for a period of time, and centrifuging to obtain the bismuth trioxide quantum dot modified black phosphorus nanosheet, namely the novel degradable black phosphorus-based X-ray photodynamic therapy photosensitizer. According to the method, the black phosphorus nanosheets are used for adsorbing bismuth ions in the solution, and the bismuth ions are hydrolyzed, so that bismuth trioxide quantum dots are formed on the surfaces of the black phosphorus nanosheets, and the stability of the black phosphorus in water can be improved. The method has the advantages of simple process, easy operation, large sample preparation amount, short time consumption, high conversion efficiency and good reproducibility, can realize low-cost large-scale industrialized production of the nano-scale black phosphorus, and does not generate the problem of secondary pollution to the environment.
3. The invention utilizes the mode that bismuth salt is hydrolyzed on the surface of the black phosphorus nanosheet to prepare the black phosphorus nanosheet modified by the bismuth trioxide quantum dots, namely the black phosphorus-based X-ray photodynamic therapy photosensitizer, compared with the original black phosphorus, the stability of the black phosphorus-based X-ray photodynamic therapy photosensitizer is obviously improved, and the black phosphorus-based X-ray photodynamic therapy photosensitizer is stable in water, but can still be degraded in a physiological environment such as a phosphate buffer solution. Compared with the traditional photosensitizer porphyrin medicine, the material can be induced by X-rays to generate singlet oxygen, and the treatment depth is large; the material can be degraded in physiological environment, and has no need of avoiding light and no phototoxicity after administration.
4. The photosensitizer grows bismuth trioxide quantum dots on the surface of black phosphorus, maintains the characteristics of the black phosphorus, and increases the stability of the black phosphorus, because the bismuth has higher atomic number and strong absorption capacity on X-rays, the bismuth trioxide quantum dots are directly contacted with the black phosphorus, when the X-rays are irradiated, the bismuth trioxide absorbs the X-rays and directly transfers partial energy to the black phosphorus nanosheets, electrons in the black phosphorus nanosheets are transferred to surrounding oxygen, and the bismuth trioxide as a semiconductor can also transfer the electrons to the surrounding oxygen to form singlet oxygen, thereby realizing the synergistic photodynamic effect.
5. The invention can realize the large-scale preparation of the biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer and lays a foundation for the application of the photosensitizer in the fields of photoelectric devices, solar cells, lithium batteries, biomedicine and the like.
Drawings
FIG. 1 is a transmission electron micrograph of a black phosphorus-based X-ray photodynamic therapy photosensitizer prepared in example 1 of the present invention.
FIG. 2 shows the stable absorption spectrum in water and the degradation absorption spectrum in phosphate buffer of the black phosphorus-based X-ray photodynamic therapy photosensitizer prepared in example 1 of the present invention; wherein, the graph A is the stable absorption spectrum of the photosensitizer in water; and the graph B shows the degradation absorption spectrum of the photosensitizer in a phosphate buffer solution.
FIG. 3 is a graph showing the photothermal temperature increase of a black phosphorus-based X-ray photodynamic therapy photosensitizer prepared in example 1 of the present invention.
FIG. 4 is a graph showing the enhanced anti-tumor effect of the photosensitizer for black phosphorus-based X-ray photodynamic therapy prepared in example 1 of the present invention.
FIG. 5 is a graph showing the enhanced singlet oxygen accumulation of the photosensitizer for black phosphorus-based X-ray photodynamic therapy prepared by example 1 of the present invention. Wherein, the graph A is the time-dependent change of singlet oxygen generated by a photosensitizer in PBS; FIG. B is a graph of the time course of singlet oxygen production by photosensitizers in PBS following X-ray radiation therapy; panel C is a graph of photosensitizer production of singlet oxygen in a375 melanoma cells over time; panel D is a graph of singlet oxygen production over time in A375 melanoma cells following photosensitizer in combination with X-ray radiation therapy.
FIG. 6 is a graph showing the effect of the black phosphorus-based X-ray photodynamic therapy photosensitizer prepared in example 1 of the present invention on tumor volume.
FIG. 7 is a graph showing the effect of the photosensitizer for black phosphorus-based X-ray photodynamic therapy prepared by example 1 of the present invention on tumor weight.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.
The black phosphorus nanosheet referred to in the embodiments of the present invention is obtained by liquid phase exfoliation of black phosphorus crystals. The method comprises the following specific steps: dispersing black phosphorus powder into an organic solvent N-methyl pyrrolidone solution, carrying out ultrasonic treatment on the black phosphorus powder for 5 hours by using a probe with the power of 1200W, carrying out ultrasonic treatment on the black phosphorus powder for 5 hours in an ice bath, centrifuging the black phosphorus powder for 15 minutes at 7000 revolutions to remove precipitates, and then centrifuging the black phosphorus powder for 15 minutes at 12000 revolutions to obtain the precipitates, namely the required black phosphorus nanosheets.
EXAMPLE 1 preparation of a Black phosphorus-based X-ray photodynamic therapy photosensitizer
A preparation method of a novel biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer comprises the following steps:
(1) dispersing the black phosphorus nanosheets in N-methyl pyrrolidone, and preparing a black phosphorus nanosheet N-methyl pyrrolidone solution with the concentration of 20 mug/mL for later use;
(2) dissolving bismuth nitrate pentahydrate in an ethylene glycol solution to prepare the ethylene glycol solution of the bismuth nitrate pentahydrate with the concentration of 25mM (the bismuth salt solution needs to be prepared fresh);
(3) taking 21mL of the black phosphorus nanosheet N-methylpyrrolidone solution obtained in the step (1), adding 3.5mL of the ethylene glycol solution of bismuth nitrate pentahydrate obtained in the step (2), uniformly mixing, standing for 3 hours in a room temperature environment, centrifuging at 12000rpm for 15 minutes, and obtaining a precipitate which is a bismuth trioxide quantum dot modified black phosphorus nanosheet, namely a biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer, marked as Bi2O3@BP。
EXAMPLE 2 preparation of a Black phosphorus-based X-ray photodynamic therapy photosensitizer
A preparation method of a novel biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer comprises the following steps:
(1) dispersing the black phosphorus nanosheets in N-methyl pyrrolidone, and preparing a black phosphorus nanosheet N-methyl pyrrolidone solution with the concentration of 10 mug/mL for later use;
(2) dissolving bismuth acetate in ethylene glycol solution to prepare ethylene glycol solution of bismuth acetate with the concentration of 20mM (bismuth salt solution needs to be prepared fresh);
(3) and (2) taking 21mL of the black phosphorus nanosheet N-methylpyrrolidone solution obtained in the step (1), then adding 2mL of the ethylene glycol solution of bismuth acetate obtained in the step (2), uniformly mixing, standing for 0.5 hour in an environment at 80 ℃, centrifuging for 15 minutes at 12000rpm, and obtaining a precipitate which is the bismuth trioxide quantum dot modified black phosphorus nanosheet.
EXAMPLE 3 preparation of a Black phosphorus-based X-ray photodynamic therapy photosensitizer
A preparation method of a novel biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer comprises the following steps:
(1) dispersing the black phosphorus nanosheets in 1, 3-dimethyl-2-imidazolidinone to prepare a black phosphorus nanosheet 1, 3-dimethyl-2-imidazolidinone solution with the concentration of 50 mug/mL for later use;
(2) dissolving bismuth acetate in N-methyl pyrrolidone solution to prepare 8mM bismuth acetate N-methyl pyrrolidone solution (bismuth salt solution needs to be prepared fresh);
(3) and (2) taking 21mL of the black phosphorus nanosheet 1, 3-dimethyl-2-imidazolidinone solution obtained in the step (1), then adding 21mL of the N-methylpyrrolidone solution of bismuth acetate obtained in the step (2), uniformly mixing, standing for 8 hours in an environment at 4 ℃, centrifuging for 15 minutes at 12000rpm, and obtaining a precipitate which is the bismuth trioxide quantum dot modified black phosphorus nanosheet.
Example 4Bi2O3Performance testing of @ BP
1. The transmission electron microscope examination of the biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer prepared in example 1 showed that a large number of quantum dots (5 ± 3nm for bismuth trioxide quantum dots) were modified on the surface of the black phosphorus sheet, which indicated that the experimental protocol was successfully implemented.
2. The biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer prepared in the example 1 is subjected to stability detection, and the method comprises the following specific steps:
the same mass (100 μ g) of the novel biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer was dispersed in 5mL of water and in phosphate buffer (phosphate buffer is usually used to simulate physiological environment), and the absorption spectrum was measured at different time points (0, 1, 2, 3, 4, 5, 6 days), as shown in fig. 2, and it was found that the photosensitizer does not substantially decrease in the absorption spectrum in water, but decreases in phosphate buffer over time, indicating that the photosensitizer of the present invention is stable in water and degradable in physiological environment.
3. The photo-thermal effect of the biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer prepared in example 1 is detected by the following specific steps:
the biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer prepared in example 1 is prepared into photosensitizer solution with the final concentration of 20ppm, 1mL of the photosensitizer solution is put into a transparent plastic EP tube, and the photosensitizer solution is used for emitting light with the wavelength of 808nm and the power of 1W/cm2The laser of (2) was irradiated for 10 minutes, the solution temperature was measured with a visible infrared thermal imager every 30 seconds, and a photothermal temperature rise curve was plotted using ultrapure water as a control, and the results are shown in FIG. 3. After 10 minutes, the temperature of the photosensitizer solution is increased from 22.7 ℃ to 55 ℃, and the temperature of ultrapure water used as a control group is only increased from 22.7 ℃ to 27.2 ℃, which shows that the photosensitizer prepared in example 1 has excellent photothermal conversion capability, is an excellent photothermal material, and has wide application prospects in the fields of photoelectric devices and biomedicine.
Example 5Bi2O3Research on in-vitro anti-melanoma activity enhanced by @ BP in cooperation with X-ray
The in vitro photodynamic therapy detection of the biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer prepared in the embodiment 1 comprises the following specific steps:
a375 melanoma cells (American model culture pool) were collected at a density of 2X 10 in logarithmic growth phase4cells/mL were seeded in 96-well plates (100. mu.L/well) and allowed to grow adherently for 24 hours. The photosensitizer solution with the final concentration of 0.3, 0.6 and 1.2 mug/mL prepared by the photosensitizer solution for the biodegradable black phosphorus-based X-ray photodynamic therapy prepared in the example 1 is added into the cells, after incubation for 6 hours, the X-ray radiation group irradiates 4Gy under an X-ray linear accelerator, then culture is continued for 72 hours, and the non-radiation group is directly cultured for 72 hours. After the time out, 25. mu.L of MTT solution (5mg/mL, PBS solution) was added to each well and incubated for 4 hours. The supernatant (DMEM high-sugar medium, Gibco) was removed from the 96-well plate, 150. mu.L DMSO (dimethyl sulfoxide) was added, and the plate was gently shaken on a shaker for 15 minutes to dissolve the purple crystals in the 96-well plate sufficiently. Then, the absorbance (OD570) of each well at 570nm was measured by a multifunctional microplate reader, and the cell viability was calculated and plotted to determine the median Inhibitory Concentration (IC)50). Cell viability (%) (OD570 experimental/OD 570 control) x 100%. The cell survival rate is shown in FIG. 4, the cell survival rate of A375 melanoma induced by single X-ray under the irradiation of 4Gy dose is 80.6%, and the Bi concentration is 0.3, 0.6 and 1.2 mug/mL2O3@ BP induction of A375 melanoma cell viability in the absence of X-ray irradiation was: 95.2%, 91.4% and 80.4%. Bi concentrations of 0.3, 0.6 and 1.2. mu.g/mL when irradiated with 4Gy of X-ray2O3The survival rate of A375 melanoma cells induced by @ BP under X-ray irradiation was: 70.7%, 66.3% and 53.7%. The results show that the biodegradable phosphorus-containing compound prepared in example 1 can be used as a photosensitizer for X-ray photodynamic therapy to enhance the growth inhibition effect of radiotherapy on A375 melanoma cells.
Theoretically, radiotherapy mainly uses high-energy radiation such as X-rays or gamma-rays to induce cells to generate a large amount of Reactive Oxygen Species (ROS) and cause DNA damage, and finally kill tumor cells. ROS mainly comprise superoxide anion (O)2-), hydrogen peroxide (H)2O2) Hydroxyl radical (HO. cndot.) and singlet oxygen (1O2). Wherein singlet oxygen is the longest due to lifetimeLong, the strongest oxidizing power and is becoming more important. We have thus examined the biodegradable black phosphorus base prepared in example 1 to induce the production of A375 melanoma cells when treated alone or in combination with X-rays1O2Amount of (reflected as a decrease in fluorescence of the DPBF probe). As shown in FIG. 5, 10. mu.g/mL of Bi in PBS solution2O3@ BP Induction of 40.8% at 60 min1O2Produced, when irradiated with X-ray at an irradiation dose of 4Gy, 10. mu.g/mL of Bi2O3@ BP Induction at 60 min1O2The yield reaches 92.5%. Then we also detected Bi2O3@ BP and X-ray induced A375 melanoma cell production1O2The amount of (c). As a result of the experiment, it was found that 10. mu.g/mL of Bi2O3@ BP induces 38.4% production by A375 melanoma cells at 60 min1O210 μ g/mL of Bi after combination with X-ray2O3@ BP induces A375 melanoma cell production at 60 min1O2The amount of (B) reaches 55.4%. These results fully illustrate that: the biodegradable black phosphorus prepared in example 1 induced more production of A375 melanoma cells under X-ray irradiation1O2Thereby enhancing the growth inhibition effect of radiotherapy on A375 melanoma cells.
Example 6Bi2O3In vivo anti-tumor activity of @ BP cooperated with X-ray enhanced tumor-bearing transplanted nude mice
The in vivo photodynamic therapy detection of the biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer prepared in the embodiment 1 comprises the following specific steps:
(1): establishing a375 human melanoma tumor-bearing transplantation nude mouse model:
60 nude mice, male, 4 weeks old, weigh about 20g (Beijing Huafukang Biotech GmbH). The purchased mice were quarantined for 10 days. During the period, the mice are checked once a day, if unhealthy animals are found, the animals are immediately removed, and healthy animals are selected for experiments. Collecting A375 human melanoma cells cultured in vitro, counting, and adjusting cell suspension concentration to 1 × 107one/mL. Fixing the nude mouse, disinfecting the skin of the groin of the nude mouse by using 75% alcohol conventionally, after the alcohol is completely volatilized, subcutaneously injecting and inoculating 0.15mL of cell suspension into the right armpit of the nude mouse, and taking care to avoid the overflow of the injection when pulling out the needle. After 10 days of cell inoculation, micro-tumor formation was observed at the needle insertion site. The long and short diameters of the tumor were measured once every other day with a vernier caliper. When the tumor grows to 75-100 mm3Then, the animals are randomly grouped into four groups, and 10 animals in each group are respectively: blank control group, X-ray radiotherapy group and Bi2O3@ BP group and Bi2O3The @ BP combined radiotherapy group.
(2) The drug treatment mode is as follows: each group of tumor-bearing transplanted nude mice is injected with drugs through tail vein, every other day, the drugs are administered for 10 times in total, each group of nude mice is killed after being broken neck after 21 days, and tumor blocks are taken out and weighed through operation. Wherein the blank control group and the X-ray radiotherapy group are injected with normal saline and Bi2O3@ BP group and Bi2O3Bi prepared by injecting normal saline into tissue of @ BP combined radiotherapy2O3@ BP, concentration 20. mu.g/mL, 100. mu.L per nude mouse tail vein injection. The formula for Tumor Volume (TV) is: TV 1/2 × a × b2Wherein a and b represent length and width, respectively.
(3) As shown in FIG. 6, it was found that the tumor volume of the control group rapidly grew with the increase of time, and the average value of the tumor volume of the control group reached 0.89cm by day 213，Bi2O3The tumor volume of the @ BP-treated mice also reached 0.97cm at day 213The results show that Bi alone2O3@ BP does not inhibit the growth of melanoma in mice. After combined X-ray radiotherapy, Bi2O3The tumor volume of the mice in the @ BP combined radiotherapy group was 0.38cm at day 213Significantly less than blank control and Bi alone2O3The @ BP group. Then, we dissected and weighed tumors of each treatment group of mice 21 days after administration. As shown in FIG. 7, blank control and Bi alone2O3The weight average of the tumors of the @ BP group mice is respectively: 1.06 g and 1.07 g, while the mean tumor weight in the radiotherapy group was 0.61 g, the results further illustrate Bi alone2O3The @ BP nanosheet cannot inhibit the growth of melanoma in a mouse body, and X-ray radiotherapy can show good curative effect. When Bi is present2O3After the mice are treated by the combination of the @ BP and the X-ray radiotherapy, the growth of the melanoma of the mice is obviously inhibited, and the average value of the tumor weight is reduced to 0.35 g. Thus, the biodegradable phosphorus base prepared in example 1 is further demonstrated to act as a photosensitizer for X-ray photodynamic therapy to enhance the growth inhibitory effect of radiotherapy on A375 melanoma in mice. This indicates that the novel photosensitizer is an excellent photosensitizer.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A preparation method of a biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer is characterized by comprising the following steps:
(1) dispersing the black phosphorus nanosheets in an organic solvent to obtain a black phosphorus nanosheet solution;
(2) dissolving bismuth salt in an organic solvent to obtain a bismuth salt solution;
(3) adding the bismuth salt solution obtained in the step (2) into the black phosphorus nanosheet solution obtained in the step (1), standing, and centrifuging to obtain a biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer;
the bismuth salt in the step (2) is soluble bismuth salt.
2. The method for preparing the biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer according to claim 1, characterized in that:
the organic solvent in the steps (1) and (2) is one or more of N-methylpyrrolidone, N, N-dimethylformamide, 1, 3-dimethyl-2-imidazolidinone, isopropanol, ethylene glycol, tetrahydrofuran and dimethyl sulfoxide.
3. The process for the preparation of the biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer according to claim 1 or 2, characterized in that:
the bismuth salt in the step (2) is one or more of bismuth nitrate pentahydrate, bismuth acetate and bismuth citrate.
4. The method for preparing the biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer according to claim 1, characterized in that:
the concentration of the black phosphorus nanosheet solution in the step (1) is 1-1000 mug/mL;
the concentration of the bismuth salt solution in the step (2) is 1-100 mM;
the volume ratio of the bismuth salt solution to the black phosphorus nanosheet solution in the step (3) is 2-21: 21.
5. the method for preparing the biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer according to claim 1, characterized in that:
the concentration of the black phosphorus nanosheet solution in the step (1) is 10-50 mug/mL;
the concentration of the bismuth salt solution in the step (2) is 8-25 mM.
6. The method for preparing the biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer according to claim 1, characterized in that:
the standing condition in the step (3) is as follows: standing for 0.5-8 hours at 4-80 ℃;
the centrifugation conditions in the step (3) are as follows: centrifuging at 8000-14000 rpm for 10-30 minutes.
7. A biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer, characterized in that: prepared by the method of any one of claims 1 to 6.
8. Use of the biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer as claimed in claim 7 in the field of photovoltaic devices, solar cells or lithium batteries.
9. Use of the biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer as defined in claim 7 for the preparation of an antitumor drug.
10. The use of the biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer as claimed in claim 9, in the preparation of an antitumor drug, characterized in that: the tumor is human melanoma, non-small cell lung cancer, human cervical cancer, human gastric cancer, human liver cancer, breast cancer, nasopharyngeal carcinoma or brain glioma.
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